Inflammation is brought about when leukocytes migrate to the site of injury in tissue, for example, tissue injured as a result of acute myocardial infarction, cardiopulmonary bypass, or stroke. In myocardial infarction, interruption of blood flow to cardiac tissue causes damage due primarily to oxygen deprivation (ischemia). When blood flow is returned (reperfusion) further damage to the ischemic tissue can occur. This reperfusion injury is to a significant extent due to neutrophils which migrate from blood vessels into the damaged tissue by interacting with adhesion molecules on the surface of the blood vessels. The neutrophils mediate inflammation, tissue necrosis, and plugging of microvasculature. An effective approach for reducing reperfusion injury is to block the interaction between neutrophils and the adhesion molecules on the blood vessel walls.
One such adhesion molecule is intracellular adhesion molecule-1 (ICAM-1), a member of the immunoglobulin (Ig) supergene family, which is expressed on activated endothelial cells on the blood vessel wall, activated T cells, activated B cells and monocytes. ICAM-1 binds to receptors known as xcex22 integrins which are found on B and T lymphocytes, monocytes, and neutrophils. The binding of ICAM-1 expressed on endothelial cells to the xcex22 integrins Mac-1 (macrophage differentiation antigen also known as CD11b/CD18, CR3, and xcex1Mxcex22) and/or LFA-1 (lymphocyte function-associated antigen-1, also known as CD11a/CD18 and xcex1Lxcex22) expressed on neutrophils activated by inflammatory mediators such as platelet activating factor (PAF) and interleukin-8 (IL-8), mediates the firm adhesion that is required before extravasation of the neutrophils into sites of inflammation. Extravasated and activated neutrophils adhere to the tissue bed, causing tissue necrosis and microvasculatory plugging. In vitro studies have demonstrated that binding of neutrophils to activated cardiac myocytes is dependent on xcex22integrins (Entman et al. J. Clin. Invest. 1990, 85, 1497-1506).
Mac-1 also binds to fibrinogen, a plasma protein that mediates platelet aggregation in the presence of platelet activating factor. The platelets bind to damaged tissue resulting in the deposition of fibrinogen on the blood vessel wall. The Mac-1-fibrinogen interaction can therefore contribute to the adhesion of neutrophils and monocytes to endothelial cells. The murine antibody 7E3, directed against the integrin xcex1IIbxcex23, also binds to the integrins xcex1vxcex23and Mac-1, and it inhibits the interaction of neutrophils with immobilized fibrinogen (Plescia et al. J. Biol. Chem. 1998, 273, 20372-20377). The humanized Fab fragment of 7E3 is approved for the prevention of ischemic complications in patients undergoing cardiac percutaneous coronary intervention.
In humans, expression of the xcex22 integrin Mac-1 is upregulated during cardiopulmonary bypass (Gillinov et al. Ann. Thorac. Surg. 1993, 56, 847-853) and in the acute phase of myocardial infarction (Meisel et al. J. Am. Coll. Card. 1998, 31,120-125). Levels of soluble ICAM-1 are also elevated in acute myocardial infarction in humans (Kaikita et al. Japanese Circ. Journal 1997, 61, 741-748).
Reduction of the interaction between ICAM-1 and its receptors decreases neutrophil migration and resulting inflammation, consequently reduces reperfusion injury caused by inflammation following acute myocardial infarction. For example, ICAM-1-deficient mice show decreased neutrophil migration in response to chemical peritonitis (Sligh et al. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8529-33) and are protected from reperfusion injury in models of stroke and renal failure (Soriano et al. Ann. Neurol. 1996, 39, 618-624; Kelly et al. J Clin. Invest. 1996, 97, 1056-63).
Antibody to ICAM-1 is protective in cat, dog, and rabbit models of cardiac reperfusion injury, and antibody to CD18 is protective in rat, rabbit, cat, dog, and various primate models of cardiac reperfusion injury (Ma et al. Circulation 1992, 86, 937-946; Lefer et al. Am. J. Physiol. 1996, 271, H2421-H2429; Zhao et al. J. Leukocyte Biol. 1997, 62, 292-300; Lefer et al. Circulation 1993, 88, 1779-1787). Biological molecules which block ICAM-1 activity, for example, antibodies to ICAM-1, CD11b and CD18, have also been shown to reduce inflammation damage in models of stroke (Zhang et al. Stroke, 1995, 26,1438-43; Chen et al. Ann. Neurol. 1994, 35, 458-63; Zhang et al. Brain Res. 1995, 698, 79-85; Bowes et al. Exp. Neurol. 1993, 119, 215-219). Antibody to CD11b is effective in attenuating neointimal growth in a rabbit model of restenosis (Rogers et al. Proc. Natl. Acad. Sci. USA 1998, 95, 10134-10137). Antibodies blocking ICAM-1 activity are the subject of International Patent Application Nos. 9302191, 9402175, 9404188, 9408620, 9412214, 9726912 and U.S. Pat. No. 5,695,760. Antisense oligonucleotides to murine ICAM-1 have been shown to attenuate reperfusion injury and renal failure in rats (Stepkowski et al. J. Immunol. 1994, 153, 5336-46; Haller et al. Kidney Int. 1996, 50, 473-480). Molecules of this type have been patented (U.S. Pat. Nos. 5,591,623 and 5,580,969).
However, compounds such as small molecule (i.e. low molecular weight) antagonists of the interaction between ICAM-1 and its ligands offer advantages over antibodies and antisense oligonucleotides for treating reperfusion injury because smaller molecules have increased tissue penetration, lack of immunogenicity, shorter half-lives, lower cost, and in general lower risks of serious adverse events. Therefore, compounds other than these biological molecules which block ICAM-1 activity are desirable as therapeutic agents for the treatment of acute inflammatory conditions such as ischemia-reperfusion injury. A number of patents and applications are directed to compounds which block ICAM-1 activity, e.g. U.S. Pat. Nos. 5,288,854, 5,530,157, 5,489,598, 5,464,855, 5,708,141, 5,707,985, International Patent Application Nos. 9640641 and 9807423.
This invention is directed to compounds which are capable of blocking ICAM activity and are accordingly particularly useful in treatment of reperfusion injury following acute myocardial infarction. Such compounds are as follows:
Compounds of formula: 
wherein R1 is a group of the formula 
where A is hydrogen, hydroxy, amino, or halogen and B is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl, or lower alkoxy;
R2 is a group of the formula 
where R3 is hydrogen, carboxy, or lower alkyl;
n is 0 or 1; U, V, and W are independently hydrogen, halogen, or lower alkyl provided U and V are not both hydrogen; X is carbonyl, phenyl-substituted loweralkylene, or sulfonyl; Y is lower alkylene which may be substituted by one or more of amino, substituted amino, loweralkyl, or cyclo lower alkyl, or Y is lower alkenylene or lower alkylenethio; k is 0 or 1; when k is 1: Z is hydrogen, lower alkylthio, xe2x80x94COOH, xe2x80x94CONH2, or amino; or when k is 0 or 1 Z is: 1-adamantyl, diphenylmethyl, 3-[[(5-chloropyridin-2-yl)amino]carbonyl]pyrazin-2-yl, and may also in addition be hydroxy, phenylmethoxy, 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]phenyl, [2,6-dichlorophenyl)methoxy]phenyl, or Z is one of the following:
cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, any of which rings may be unsubstituted, or substituted with at least one of:
halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, unsubstituted lower alkyl, halogen-substituted lower alkyl, lower alkoxy-substituted lower alkyl, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, alkoxycarbonyl, acetoxy, or also in addition with amino lower alkyl and pharmaceutically acceptable salts and esters thereof,
compounds of the formula: 
wherein R12 is a group of the formula 
xe2x80x83R32 is hydrogen, carboxy, or lower alkyl; U2, V2, and W2 are independently hydrogen, halogen, or is lower alkyl provided U2 and V2 are not both hydrogen; X is carbonyl, phenyl-substituted loweralkylene, or sulfonyl; Y2 is lower alkenylene, lower alkylenethio, or is lower alkylene which may be substituted by amino, acetylamino, or cyclo-lower alkyl; k2 is 0 or 1; when k2 is 1, Z2 is: hydrogen, lower alkylenethio,
xe2x80x94COOH, xe2x80x94CONH2, or amino; or when k2 is 0 or 1, Z is: 1-adamantyl, diphenylmethyl, 3-[[(5-chloropyridin-2-yl)amino]carbonyl]pyrazin-2-yl, or Z2 is one of the following: cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, any of which rings may be unsubstituted, or substituted with at least one of: halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, lower alkyl unsubstituted halogen or substituted lower alkyl, lower alkoxy-substituted lower alkyl, slower alkoxy, carboxy, alkoxycarbonyl, or acetoxy; and pharmaceutically acceptable salts and esters thereof,
compounds of the formula 
wherein A3 is hydrogen, hydroxy, amino, or halogen and B3 is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl, or lower alkoxy;
R23 is a group of the formula 
where R33 is hydrogen, carboxy, or lower alkyl; U3, V3, and W3 are independently hydrogen, halogen, or lower alkyl provided U3 and V3 are not both hydrogen; and R4 is hydrogen, lower alkyl, or aryl-lower-alkyl which can be unsubstituted or substituted with at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, hydroxy, aryl, aryloxy, unsubstituted lower alkyl, halogen substituted lower alkyl, lower alkoxy-substituted lower alkyl, lower alkoxy, carboxy, alkoxycarbonyl, or acetoxy and pharmaceutically acceptable salts and esters thereof,
and prodrug compounds of the formula 
wherein R1, R2, n, U, V, W, X, Y, k, and Z are as in formula 1a; R6 is lower alkyl or
xe2x80x94CH2CH2xe2x80x94R7 where R7 is xe2x80x94N(CH3)2, 
xe2x80x83where R8 is hydrogen or methyl and R9 is lower alkyl or lower cycloalkyl; and pharmaceutically acceptable salts and esters thereof.
This invention is also directed to pharmaceutical compositions and methods of treatment using the above compounds.